Protection against doxorubicin-induced cardiomyopathy

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Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-13
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project Description:
Doxorubicin (DOX) is a potent and effective chemotherapeutic agent belonging to the anthracycline class of antibiotics. It is used frequently in the treatment of many hematologic and solid tumor malignancies. Despite its clinical efficacy, DOX's use is often limited by its potential for causing dose-dependent cardiotoxicity. Our recent studies have shown that potent phosphodiesterase-5A (PDE-5A) inhibitor, sildenafil citrate (Viagra), which is known to enhance erectile function in men, induces powerful cardioprotective effect against ischemia-reperfusion injury (I/R) in the rabbit and mouse hearts. The purpose of this application is to show the effect of class of novel PDE-5A inhibitors on DOX-induced cardiomyocyte apoptosis and to understand signaling pathways which leads to a long lasting cardioprotection. We will test the following hypotheses: 1) Suppression ofPDE-5A with novel class of inhibitors attenuate DOX-inducedcardiotoxicity andcontractile dysfunction via inhibition of cardiomyocyte apoptosis in the heart. We will also determine the effect of PDE-5 inhibitors onanti-tumor properties of DOX. 2). PDE-5A inhibitors) trigger signaling mechanismsinvolving activation of transcription factor, GATA-4, which leads to enhanced expression ofBcl-2 and attenuate cardiomyocytes apoptosis following DOX-treatment 3) PDE-5A inhibitors stimulate guanylate cyclase and elevate cGMP causing activationof protein kinase G(PKG)leading to attenuationof DOX-induced cardiotoxicity. 4) PDE-5A inhibitors drive the expression of heat shockproteins through gene transcription andactivation of heat shock transcription factor-1 which mayresult in reduction of DOX-induced cardiotoxicity in the heart. This study will be the first one to demonstrate the protective effect of PDE-5A inhibitors in DOX-induced cardiotoxicity in the heart at cellular and sub-cellular level. These studies will also provide valuable information leading to eventual clinical trials in humans receiving DOX-chemotherapy for hematologic and/or oncologic neoplasms.
 
Project Terms:
(+)-(S)-4,4'-(1-Methyl-1,2-ethanediyl)di(2,6-piperazinedione) (8S-cis)-10-[(3-Amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroacetyl)-1-methoxy-5,12-naphthacenedione 1-(((3-(3,4-dihydro-5-methyl)-4-oxo-7-propylimidazo(5,1-f)-as-triazin-2-yl)-4-ethoxyphenyl)sulfonyl)-4-ethylpiperazine 1-((3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-methylpiperazine citrate 1-Phosphatidylinositol 3-Kinase 14-Hydroxydaunomycin 2,6-Piperazinedione, 4,4'-(1-methyl-1,2-ethanediyl)bis-,(S)-(9CI) 2,6-Piperazinedione, 4,4'propylenedi-,(P)-(8CI) 5,12-Naphthacenedione, 10-((3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, (8S-cis)- ADP-Ribosyltransferase (Polymerizing) APAETP ATP[{..}]1-phosphatidyl-1D-myo-inositol 3-phosphotransferase Abbott brand of sildenafil citrate Abbreviations Active Oxygen Acute Adenosine Adriamycine Alza Brand of Amifostine Amifostine Aminopropylaminoethylthiophosphoric Acid Anthracycline Antibiotics Anthracyclines Antibiotic Agents Antibiotic Drugs Antibiotics Apoptosis Apoptosis Pathway Apoptotic Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Attenuated Biochemistry Blood Circulation Bloodstream Body Weight decreased Bone Tumor Bone neoplasms Bradykinin Breast Cade Cancer of the Ovary Cancers Cardiac Cardiac Failure Congestive Cardiac Myocytes Cardiac Toxicity Cardiocyte Cardiomyopathies Cardiotoxicity Cardiovascular Diseases Cations Cell Communication and Signaling Cell Culture Techniques Cell Death, Programmed Cell Signaling Cessation of Treatment Chemistry, Biological Chemosensitization Chemosensitization/Potentiation Chemotherapy, Cancer, Anthracyclines Chronic Ciclosporin Circulation Clinical Clinical Trials Clinical Trials, Unspecified Closure by Ligation Congestive Heart Failure CsA Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cyclosporin A Cyclosporine Cyclosporine A DNA Binding DNA Binding Interaction DNA Molecular Biology DOX Data Deoxyguanylate Cyclase Development Dexrazoxane Disadvantaged Dose Doxorubicin Doxorubicina Drugs Dysfunction EC 2.7 Enzymes Erectile dysfunction Essex Brand of Amifostine Ethanethiol, 2-((3-aminopropyl)amino)-, dihydrogen phosphate (ester) Ethiofos Ethyol Functional disorder G-Proteins GTP pyrophosphate-lyase (cyclizing) GTP-Binding Proteins GTP-Regulatory Proteins Gammaphos Gastric lymphoma Gene Transcription Gene Transfer Generations Genes Genetic Transcription Guanine Nucleotide Coupling Protein Guanine Nucleotide Regulatory Proteins Guanosine Cyclic 3',5'-Monophosphate Guanosine Cyclic 3',5'-Phosphate-Dependent Protein Kinase Guanosine Cyclic Monophosphate Guanosine Cyclic Monophosphate-Dependent Protein Kinases Guanosine, cyclic 3',5'-(hydrogen phosphate) Guanyl Cyclase Guanylate Cyclase HDL HSP Heart Heart Decompensation Heart Failure, Congestive Heart failure Heart myocyte Heat shock proteins Heating Heavy Lipoproteins High Density Lipoproteins High density lipoprotein Human Human, General Hydroxyl Daunorubicin Hydroxyldaunorubicin In Situ In Vitro Inosinate Cyclase Intracellular Communication and Signaling Investigation Investigators Ischemia-Reperfusion Injury Ischemic Preconditioning Juniperus oxycedrus K element Kaposi - Kaposi's Sarcoma Kaposi Sarcoma Kaposi?s Sarcoma Kinases Lead Ligation Lilly Brand of Amifostine Link Lipoproteins, HDL Lymphoma of the Stomach MMC Malignant Neoplasms Malignant Ovarian Neoplasm Malignant Ovarian Tumor Malignant Tumor Malignant Tumor of the Ovary Malignant neoplasm of ovary Mammals, Mice Mammals, Rabbits Man (Taxonomy) Man, Modern Mediator Mediator of Activation Mediator of activation protein Medication Membrane Potentials Methods and Techniques Methods, Other Mice Miscellaneous Antibiotic Mitochondria Modeling Molecular Biology Mortality Mortality Vital Statistics Multiple Hemorrhagic Sarcoma Murine Mus Muscle Cells Muscle Cells, Cardiac Muscle Cells, Heart Muscle Cells, Mature Mycocardium Disease Myelosuppression Myocardial Myocardial Diseases Myocardial Disorder Myocardiopathies Myocytes Myocytes, Cardiac NAD+[{..}]poly(adenosine diphosphate D-ribose)-acceptor ADP-D-ribosyltransferase Neoplasms Oligo Oligonucleotides Oryctolagus cuniculus Osseous Neoplasm Osseous Tumor Oxygen Radicals PARP Polymerase PARS PDE PDE4 enzyme PDase IV PI-3 Kinase PI-3K PI3-Kinase PKG Patients Pb element Pfizer brand of sildenafil citrate Pharmaceutic Preparations Pharmaceutical Preparations Phenol, 4,4'-((1-methylethylidene)bis(thio))bis(2,6-bis(1,1-dimethylethyl))- Phosphatidylinositol 3-Kinase Phosphatidylinositol-3-OH Kinase Phosphodiesterases Phosphoinositide 3-Hydroxykinase Phosphorylation Phosphotransferases Physiologic Physiological Physiology Physiopathology Play Poly(ADP-Ribose) Synthase Poly(ADP-Ribose) Transferase Poly(ADP-ribose) Polymerases Poly(ADPR) Polymerase Poly(ADPribose) Polymerase Potassium Potentiation Preconditionings, Ischemic Pro-Oxidants Probucol Programs (PT) Programs [Publication Type] Property Property, LOINC Axis 2 Protein Kinase G Protein Phosphorylation PtdIns 3-Kinase RNA Expression RNA, Small Interfering Rabbit, Domestic Rabbits Reactive Oxygen Species Regulation Reperfusion Damage Reperfusion Injury Research Personnel Researchers Resting Potentials Role S-(N-(3-Aminopropyl)-2-aminoethyl)thiophosphoric Acid Sandimmun SangCya Schering-Plough Brand of Amifostine Series Signal Pathway Signal Transduction Signal Transduction Systems Signaling Sildenafil citrate Silenafil Citrate Small Interfering RNA Solid Neoplasm Solid Tumor Soluble ICRF (L-isomer) Stress Stress Proteins Techniques Testing Topoisomerase II inhibition Transcription Transcription, Genetic Transmembrane Potentials Transphosphorylases Tumors Type I Phosphatidylinositol Kinase Type III Phosphoinositide 3-Kinase US Bioscience Brand of Amifostine Viagra Weight Loss Weight Reduction Withholding Treatment alpha-Lipoproteins anthracycline attenuation biological signal transduction body weight loss cGMP cGMP kinase cGMP-Dependent Protein Kinases cardiac failure cardiomyocyte cardiovascular disorder chemotherapeutic agent chemotherapy clinical efficacy clinical investigation clinical relevance clinically relevant cyclosporin A-SPTP cyclosporin A-sensitive pereability transition pore drug/agent guanosine 3'5'monophosphate guanylyl cyclase heat shock transcription factor heavy metal Pb heavy metal lead in vivo in vivo Model indexing inhibitor inhibitor/antagonist insight kallidin 9 kallidin I malignancy men men's mitoK(ATP) mitoKATP mitochondrial mitochondrial K(ATP) channel mitochondrial megachannel mitochondrial membrane mitochondrial permeability transition pore mouse model myocardium disorder neoplasia neoplasm/cancer neoplastic neoplastic growth neoral novel ovarian cancer pathophysiology phosphodiesterase 4 phosphodiesterase IV phosphoric diester hydrolase poly ADP polymerase poly ADP ribose synthetase preconditioning prevent preventing programs protective effect receptor-mediated signaling sandimmune siRNA sildenafil social role tadalafil transcription factor transfer of a gene tumor type 4 cyclic nucleotide phosphodiesterase vardenafil wt-loss
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-13
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project Categories:
• Natural Sciences > Aging Diseases and Pathology > Cardiovascular and cerebrovascular diseases > Cardiomyopathy
 
Other Information:
Fiscal Year: 1995
Project Start Date: 1 August 1995
Project End Date: 31 December 2010
Administering Institute Or Center: HL
 
Project Funding Information:
Total Funding: $354,561
Year Funding Organization Total Funding, $
2009 NATIONAL HEART, LUNG, AND BLOOD INSTITUTE $354,561
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-13
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-13
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project number Project title Organization FY Funding Organization FY Total Cost
5R01HL059469-07Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2004NATIONAL HEART
$375,000
5R01HL051045-09SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2004NATIONAL HEART
$290,000
5R01HL059469-06Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2003NATIONAL HEART
$375,000
5R01HL051045-08SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2003NATIONAL HEART
$290,000
2R01HL059469-05Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2002NATIONAL HEART
$375,000
5R01HL051045-07SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2002NATIONAL HEART
$290,000
5R01HL059469-04MOLECULAR MECHANISMS OF DELAYED PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2001NATIONAL HEART
$265,698
5R01HL051045-06SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2001NATIONAL HEART
$290,000
5R01HL059469-03MOLECULAR MECHANISMS OF DELAYED PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2000NATIONAL HEART
$258,001
2R01HL051045-05SIGNALING MECHANISMS IN PHARMACOLOGICAL PRECONDITIONINGVIRGINIA COMMONWEALTH UNIVERSITY2000NATIONAL HEART
$281,900
5R01HL059469-08Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2005NATIONAL HEART
$375,000
1R01HL079424-01CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2005NATIONAL HEART
$454,713
5R01HL059469-09Molecular Mechanisms of Delayed PreconditioningVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$366,188
5R01HL079424-02CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$440,694
2R37HL051045-10Protection against Doxorubicin-Induced CardiomyopathyVIRGINIA COMMONWEALTH UNIVERSITY2006NATIONAL HEART
$365,640
5R01HL079424-03CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2007NATIONAL HEART
$450,503
5R37HL051045-11Protection against Doxorubicin-Induced CardiomyopathyVIRGINIA COMMONWEALTH UNIVERSITY2007NATIONAL HEART
$361,698
5R01HL079424-04CARDIOPROTECTIVE EFFECTS OF PDE-5 INHIBITORSVIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$454,221
1R01HL093685-01Cardioprotective Signaling following Phosphodiesterase-5 InhibitionVIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$372,500
1R25HL092622-01Health Educational Research Opportunities (HERO)VIRGINIA COMMONWEALTH UNIVERSITY2008NATIONAL HEART
$93,118
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-13
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Protection against doxorubicin-induced cardiomyopathy
Principal Investigators (PI): KUKREJA RAKESH C
Project Number: 5R37HL051045-13
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
 
Title Abstract Authors Year Rel
A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70. Circulation research. 2009 Mar 13 104 (5) :572-5 Yin, Chang; Salloum, Fadi N; Kukreja, Rakesh C 2009
cis-3, 4', 5-Trimethoxy-3'-aminostilbene disrupts tumor vascular perfusion without damaging normal organ perfusion. Cancer chemotherapy and pharmacology. 2009 Jan 63 (2) :191-200 Durrant, David; Corwin, Frank; Simoni, Daniele; Zhao, Ming; Rudek, Michelle A; Salloum, Fadi N; Kukreja, Rakesh C; Fatouros, Panos P; Lee, Ray M 2009
Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase g-dependent generation of hydrogen sulfide. Circulation. 2009 Sep 15 120 (11 Suppl) :S31-6 Salloum, Fadi N; Chau, Vinh Q; Hoke, Nicholas N; Abbate, Antonio; Varma, Amit; Ockaili, Ramzi A; Toldo, Stefano; Kukreja, Rakesh C 2009
cGMP-hydrolytic activity and its inhibition by sildenafil in normal and failing human and mouse myocardium. The Journal of pharmacology and experimental therapeutics. 2009 Sep 330 (3) :884-91 Vandeput, Fabrice; Krall, Judith; Ockaili, Ramzi; Salloum, Fadi N; Florio, Vincent; Corbin, Jackie D; Francis, Sharron H; Kukreja, Rakesh C; Movsesian, Matthew A 2009
ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice. American journal of physiology. Heart and circulatory physiology. 2009 May 296 (5) :H1236-43 Das, Anindita; Salloum, Fadi N; Xi, Lei; Rao, Yuan J; Kukreja, Rakesh C 2009